Dietary and Pharmacologic Manipulations of Host Lipids and Their Interaction With the Gut Microbiome in Non-human Primates

Jennifer M Lang; Leslie R Sedgeman; Lei Cai; Joseph D Layne; Zhen Wang; Calvin Pan; Richard Lee; Ryan E Temel; Aldons J Lusis

doi:10.3389/fmed.2021.646710

Dietary and Pharmacologic Manipulations of Host Lipids and Their Interaction With the Gut Microbiome in Non-human Primates

Front Med (Lausanne). 2021 Aug 26:8:646710. doi: 10.3389/fmed.2021.646710. eCollection 2021.

Authors

Jennifer M Lang¹, Leslie R Sedgeman², Lei Cai³, Joseph D Layne^{3

4}, Zhen Wang⁵, Calvin Pan¹, Richard Lee⁶, Ryan E Temel^{4

7}, Aldons J Lusis¹

Affiliations

¹ Departments of Medicine, Microbiology and Human Genetics, University of California, Los Angeles, Los Angeles, CA, United States.
² Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, CA, United States.
³ Cardiovascular Research Center, University of Kentucky, Lexington, KY, United States.
⁴ Cardiovascular and Metabolic Diseases, Novartis Institutes for Biomedical Research, Cambridge, MA, United States.
⁵ Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China.
⁶ Ionis Pharmaceuticals, Carlsbad, CA, United States.
⁷ Department of Physiology, University of Kentucky, Lexington, KY, United States.

Abstract

The gut microbiome influences nutrient processing as well as host physiology. Plasma lipid levels have been associated with the microbiome, although the underlying mechanisms are largely unknown, and the effects of dietary lipids on the gut microbiome in humans are not well-studied. We used a compilation of four studies utilizing non-human primates (Chlorocebus aethiops and Macaca fascicularis) with treatments that manipulated plasma lipid levels using dietary and pharmacological techniques, and characterized the microbiome using 16S rDNA. High-fat diets significantly reduced alpha diversity (Shannon) and the Firmicutes/Bacteroidetes ratio compared to chow diets, even when the diets had different compositions and were applied in different orders. When analyzed for differential abundance using DESeq2, Bulleidia, Clostridium, Ruminococcus, Eubacterium, Coprocacillus, Lachnospira, Blautia, Coprococcus, and Oscillospira were greater in both chow diets while Succinivibrio, Collinsella, Streptococcus, and Lactococcus were greater in both high-fat diets (oleic blend or lard fat source). Dietary cholesterol levels did not affect the microbiome and neither did alterations of plasma lipid levels through treatments of miR-33 antisense oligonucleotide (anti-miR-33), Niemann-Pick C1-Like 1 (NPC1L1) antisense oligonucleotide (ASO), and inducible degrader of LDLR (IDOL) ASO. However, a liver X receptor (LXR) agonist shifted the microbiome and decreased bile acid levels. Fifteen genera increased with the LXR agonist, while seven genera decreased. Pseudomonas increased on the LXR agonist and was negatively correlated to deoxycholic acid, cholic acid, and total bile acids while Ruminococcus was positively correlated with taurolithocholic acid and taurodeoxycholic acid. Seven of the nine bile acids identified in the feces significantly decreased due to the LXR agonist, and total bile acids (nmol/g) was reduced by 62%. These results indicate that plasma lipid levels have, at most, a modest effect on the microbiome, whereas bile acids, derived in part from plasma lipids, are likely responsible for the indirect relationship between lipid levels and the microbiome.

Keywords: bile acids; high-fat diet; lipids; microbiome; primate.

Abstract

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